Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Biotecnologie Cellulari ed Ematologia, Sezione di Genetica Molecolare, Università di Roma La Sapienza, Viale Regina Elena 324, Roma 00161, Italy.
Nucleic Acids Res. 2012 Sep 1;40(17):8266-75. doi: 10.1093/nar/gks619. Epub 2012 Jun 26.
The bHLH transcription factor MyoD, the prototypical master regulator of differentiation, directs a complex program of gene expression during skeletal myogenesis. The up-regulation of the cdk inhibitor p57kip2 plays a critical role in coordinating differentiation and growth arrest during muscle development, as well as in other tissues. p57kip2 displays a highly specific expression pattern and is subject to a complex epigenetic control driving the imprinting of the paternal allele. However, the regulatory mechanisms governing its expression during development are still poorly understood. We have identified an unexpected mechanism by which MyoD regulates p57kip2 transcription in differentiating muscle cells. We show that the induction of p57kip2 requires MyoD binding to a long-distance element located within the imprinting control region KvDMR1 and the consequent release of a chromatin loop involving p57kip2 promoter. We also show that differentiation-dependent regulation of p57kip2, while involving a region implicated in the imprinting process, is distinct and hierarchically subordinated to the imprinting control. These findings highlight a novel mechanism, involving the modification of higher order chromatin structures, by which MyoD regulates gene expression. Our results also suggest that chromatin folding mediated by KvDMR1 could account for the highly restricted expression of p57kip2 during development and, possibly, for its aberrant silencing in some pathologies.
bHLH 转录因子 MyoD 是分化的典型主调控因子，在骨骼肌发生过程中指导复杂的基因表达程序。细胞周期蛋白依赖性激酶抑制剂 p57kip2 的上调在肌肉发育以及其他组织中协调分化和生长抑制中起着关键作用。p57kip2 表现出高度特异性的表达模式，并受到复杂的表观遗传控制，驱动父本等位基因的印迹。然而，其在发育过程中表达的调控机制仍知之甚少。我们发现了一种意想不到的机制，即 MyoD 在分化的肌肉细胞中调节 p57kip2 的转录。我们表明，p57kip2 的诱导需要 MyoD 结合位于印迹控制区 KvDMR1 内的远距离元件，随后涉及 p57kip2 启动子的染色质环释放。我们还表明，p57kip2 的分化依赖性调节虽然涉及印迹过程中涉及的区域，但与印迹控制不同，并且是分层从属的。这些发现强调了一种新的机制，即 MyoD 通过修饰高级染色质结构来调节基因表达。我们的结果还表明，KvDMR1 介导的染色质折叠可能解释了 p57kip2 在发育过程中受到高度限制的表达，并且可能解释了其在某些病理情况下异常沉默的原因。
